A highly effective one-pot Friedländer quinoline synthesis from o-nitroarylcarbaldehydes and ketones or aldehydes was developed and the scope and limitations of the method were examined. The o-nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of a catalytic amount of aqueous hydrochloric acid; the amino compounds were then condensed in situ with ketones or aldehydes to form mono-or disubstituted quinolines, respectively, in good-to-excellent yields (58-100%).Quinolines are an important class of heterocycles that have long been used antimalarial agents, 1 and more recently have been used as protein kinase inhibitors for the treatment of cancer. 2 These beneficial biological activities continue to make quinolines attractive targets for both synthetic and medicinal chemists. Among the many methods available for constructing the quinoline ring, the Friedländer quinoline synthesis has proven to be a very powerful tool. 3 This reaction typically requires two steps: reduction of an o-nitro aldehyde or ketone I into an o-amino aldehyde or ketone II followed by condensation of this intermediate with a ketone or aldehyde III (Scheme 1).Often the amino carbonyl intermediate II is unstable, especially when R 2 = H, and it may undergo self-condensation. To overcome this potential problem and make this century-old reaction more practical, several laboratories have attempted to develop one-pot procedures involving the use of II generated in situ. 4,5 Of particular interest is the one-pot method developed by Miller and McNaughton, 4a which uses a tin(II) chloride/zinc chloride system to convert o-nitro aldehydes or ketones into 2-monosubstituted or 2,3-disubstituted quinolines. This method works well with a range of aliphatic ketones but, unfortunately, it is not applicable to aromatic ketones such as acetophenone. 5 We therefore attempted to develop a method that would permit the preparation of 2-aryl-substituted quinolines. As reported in our previous preliminary communication, 5 we have discovered a practical one-pot Friedländer quinoline synthesis that uses inexpensive and readily available reagents such as iron powder, aqueous hydrochloric acid, and solid potassium hydroxide. Our method successfully condensed a variety of o-nitro aldehydes (or ketones) with various carbonyl co-reactants. Herein, we report a study of the scope and limitations of the one-pot Friedländer quinoline synthesis.In a typical operation, 2-nitrobenzaldehyde was reduced with 4.0 equivalents of iron powder in the presence of 5 mol% of aqueous hydrochloric acid in refluxing ethanol. The reduction was usually complete within 30-40 minutes (as monitored by thin-layer chromatography). After this time, 1.0 equivalents of a carbonyl compound and 1.2 equivalents of powdered potassium hydroxide were added. The mixture was then stirred at reflux for a further 40-60 minutes to complete the condensation reaction. A classical aqueous workup followed by chromatography over silica gel or by recrystallization afforded the desir...

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